NZ623815B2 - Compositions for the treatment of rheumatoid arthritis and methods of using same - Google Patents

Abstract

The disclosure relates to a method of treating rheumatoid arthritis in a subject previously treated by administering methotrexate, leflunomide, sulfasalazine and/or hydroxychloroquine, comprising administering to the subject an effective amount of sarilumab (SAR153191). The subject may have been treated with an anti-TNF-a antagonist for at least 3 months in the last 2 years or the subject may have been intolerant to at least one TNF-a antagonist. ated with an anti-TNF-a antagonist for at least 3 months in the last 2 years or the subject may have been intolerant to at least one TNF-a antagonist.

Description

COMPOSITIONS FOR THE TREATMENT OF RHEUMATOID ARTHRITIS AND METHODS OF USING SAME FIELD OF THE INVENTION The present invention relates to the field of therapeutic treatment of rheumatoid arthritis. More ically, the invention relates to the use of interleukin-6 receptor (lL—GR) antagonists, such as anti-lL-6R antibodies combined with disease ing antirheumatic drugs, to treat toid arthritis.

OUND It is estimated that approximately 0.5% to 1% of the adult population in North a and Europe is affected by rheumatoid arthritis (RA). RA affects women twice as often as men and the incidence is highest among women over 40 years of age.

RA is characterized by persistent synovitis and ssive destruction of cartilage and bone in multiple joints. The hallmark of the disease is a symmetric polyarthritis characteristically involving the small joints of the hands and feet. The inflammatory process can also target other , characteristically bone marrow a), eye (scleritis, episcleritis), lung (interstitial pneumonitis, pleuritis), cardiac (pericarditis) and skin (nodules, leukocytoclastic vasculitis).

Systemic inflammation is characterized by laboratory abnormalities, such as anemia, elevated erythrocyte sedimentation rate, fibrinogen and C—reactive protein (CRP) and by clinical symptoms of fatigue, weight loss, muscle atrophy in affected joint areas. The presence of polyclonal high—titer rheumatoid factors and anticyclic citrullinated peptide CCP) antibodies provides evidence of immune dysregulation. it has been estimated that 65% to 70% of RA ts have progressive disease that leads to joint destruction, disability and premature death.

There is a need in the art for improved treatment ns for the improvement of symptoms associated with RA.

SUMMARY The present disclosure provides a use of an antibody or binding fragment thereof in the manufacture of at least one medicament for the treatment of rheumatoid arthritis in a subject previously ineffectively treated for rheumatoid arthritis by the administration of methotrexate and previously treated ineffectively for rheumatoid arthritis by the administration of a TNF -α nist, wherein the d y or binding fragment thereof comprises the heavy chain variable region of SEQ ID No. 2 and the light chain le region of SEQ ID No. 3, and wherein the at least one medicament is formulated for administration to the patient in a dosing regime that pro vides n 100 mg and 200 mg of said antibody or binding fragment thereof, to the t; the dosing regime comprises at least one dosing cycle that is designed to provide the effective delivery of the at least one medicament in an effective amount per two weeks, and the dosing cycle is repeated for as long as necessary to achieve a desired biological response in a subject.

Throughout this specification, the term “comprises/comprising” and tical ions thereof when used in this specification a re to be taken to specify the presence of stated features, integers, steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

The use includes manufact ure of a ment including an effective amount of sarilumab (SAR153191) and a member of the group consisting of leflunomide, sulfasalazine and hydroxychloroquine. In certain ments, the subject was previously ineffectively d for rheumatoid a rthritis by administering a TNF -α antagonist. Specifically, subject could have been treated for at least three months with the TNF -α antagonist or could have been intolerant of the TNF -α antagonist. The TNF -α antagonist could be etanercept, infliximab, adalimumab, golimumab or certolizumab. In other embodiments, the subject was previously ineffectively treated for rheumatoid arthritis by administering methotrexate.

The sarilumab could be administered using the medicament at between 50 and 150 mg per we ek or between 100 and 200 mg per two weeks.

In certain ic embodiments, the medicament includes sarilumab and leflunomide . The leflunomide can be administer ed orally. The leflunomide can also be administered using the medicament at between 10 and 2 0 mg per day to the subject.

In other specific embodiments, the medicament includes for sarilumab and sulfasalazine administration. The sulfasalazine can be administered orally. The sulfasalazine can also be administered using the medicament at between 1 000 to 3000 mg per day to the subject.

In other ic embodiments, sarilumab and ychloroquine are administered to the subject using the medicament. The hydroxychloroquine can be administered orally. The hydroxychloroquine can also be administere d at between 200 to 400 mg per day to the subject using the medicament.

In some embodiments, as a result of the treatment using the medicament using the medicament the subject achieves a 20% or 50% improvement in the American College of Rheumatology core s et e index after 12 weeks of treatment. In other embodiments, as a result of the treatment, the subject achieves a 20%, 50% or 70% improvement in the an College of Rheumatology core set e index after 24 weeks of treatment.

In some embodi ments, as a result of the treatment using the medicament the subject achieves a lower disease activity score after 12 weeks of treatment than the subject had before ent. The disease ty score can be less than or equal to 2.6 at 12 weeks. The d isease activity score can decrease by greater than 1.2 between start of treatment and 12 weeks. The disease activity score can be less than or equal to 3.2 at 12 weeks. The disease activity score can decrease by r than 0.6 between start of treatmen t and 12 weeks. The disease activity score can be less than or equal to 5.1 at 12 weeks.

In some embodiments, as a result of the treatment, using the medicament the subject achieves a lower e activity score after 24 weeks of treatment than the sub ject had before treatment. The disease activity score can be less than or equal to 2.6 at 24 weeks. The disease activity score can se by greater than 1.2 between start of treatment and 24 weeks. The disease activity score can be less than or equal to 3.2 at 24 weeks.

The disease ty score can decrease by greater than 0.6 between start of treatment and 24 weeks. The disease activity score can be less than or equal to 5.1 at 24 weeks.

The present disclosure also provides a method of treating rheumatoid tis in a subject in need thereof comprising administering to the subject an effective amount of sarilumab and methotrexate, wherein the subject was previously ineffectively treated for rheumatoid arthritis by administering an anti—TNF-d eutic. In certain embodiments, the subject was previously ineffectively treated for rheumatoid arthritis by administering methotrexate. The methotrexate can be administered at between 10 to mg per week to the subject.

In certain embodiments, the t Is a mammal. The mammal can be a human. In certain ments, the human ls ded from individuals from Asia or the Pacific. Humans descended from individuals from Asia or the Pacific can be administered between 6 and 25 mg per week of methotrexate.

In certain embodiments, the subject was usly ineffectively treated for rheumatoid arthritis by administering a TNF-d antagonist. Specifically, subject could have been d for at least three months with the TNF-d antagonist or could have been intolerant of the TNF—d antagonist. The TNF-d antagonist could be etanercept, infliximab, adalimumab, mab or certollzumab. In other embodiments, the subject was previously ineffectively treated for rheumatoid arthritis by administering methotrexate.

The sarilumab could be administered at between 50 and 150 mg per week or between 100 and 200 mg per two weeks.

In some embodiments, as a result of the treatment, the subject achieves a 20% or 50% improvement in the American College of Rheumatology core set disease index after 12 weeks of treatment. In other embodiments, as a result of the treatment, the subject achieves a 20%, 50% or 70% improvement in the American College of Rheumatology core set disease index after 24 weeks of treatment.

In some embodiments, as a result of the treatment, the subject achieves a lower disease activity score after 12 weeks of treatment than the subject had before ent. The disease activity score can be less than or equal to 2.6 at 12 weeks.

The disease activity score can se by greater than 1.2 between start of treatment and 12 weeks. The disease activity score can be less than or equal to 3.2 at 12 weeks.

The disease activity score can decrease by greater than 0.6 between start of treatment and 12 weeks. The disease activity score can be less than or equal to 5.1 at 12 weeks.

In some embodiments, as a result of the treatment, the subject achieves a lower disease activity score after 24 weeks of treatment than the subject had before treatment. The disease activity score can be less than or equal to 2.6 at 24 weeks.

The disease activity score can decrease by greater than 1.2 between start of treatment and 24 weeks. The e activity score can be less than or equal to 3.2 at 24 weeks.

The disease activity score can decrease by greater than 0.6 n start of treatment and 24 weeks. The e activity score can be less than or equal to 5.1 at 24 weeks.

The disclosure also provides a pharmaceutical composition comprising an effective amount of sarilumab and a member of the group ting of leflunomide, sulfasalazine and ychloroquine. The sarilumab could be present at between 50 and 150 mg per dose or between 100 and 200 mg per dose.

In certain specific embodiments, the composition includes sarilumab and omide. The Ieflunomide can be present in an oral dosage form. The Ieflunomide can be present in the composition at between 10 and 20 mg per dose.

In other specific embodiments, the composition includes sarilumab and sulfasalazine. The sulfasalazine can be present in an oral dosage form. The sulfasalazine can be present in the composition at between 1000 to 3000 mg per day to the subject.

In other specific ments, the composition es sarilumab and hydroxychloroquine. The hydroxychloroquine can be present in an oral dosage form.

The hydroxychloroquine can be present in the composition at between 200 to 400 mg per day to the subject. es of embodiments of the invention are listed below: Embodiment 12A method of treating rheumatoid arthritis in a subject in need thereof comprising administering to the subject an effective amount of mab (SAR153191) and a member of the group consisting of leflunomide, sulfasalazine and hydroxychloroquine.

Embodiment 2: The method of embodiment 1, wherein the subject was usly ineffectively treated for rheumatoid arthritis by administering a TNF-d antagonist.

Embodiment 3: The method of embodiment 2, wherein the TNF-d antagonist is a biologic anti-TN F-d antagonist.

Embodiment 4: The method of embodiment 2 or 3, wherein the subject was d for at least three months with the TNF-d antagonist.

Embodiment 5: The method of embodiment 2 or 3, wherein the subject was rant of the TNF-d nist.

Embodiment 6: The method of embodiment 2 or 3, wherein the TNF-a antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab and certolizumab.

Embodiment 7: The method of embodiment 2 or 3, wherein the subject was previously ineffectively treated for rheumatoid arthritis by administering rexate.

Embodiment 8: The method of embodiment 1, n the sarilumab is administered at between 50 and 150 mg per week. ment 9: The method of embodiment 1, wherein the sarilumab is administered at between 100 and 200 mg per two weeks.

Embodiment 10: The method of embodiment 1, wherein sarilumab and leflunomide are administered to the subject. ment 11: The method of embodiment 10, wherein the leflunomide is administered orally.

Embodiment 12: The method of embodiment 10, wherein the leflunomide is administered at between 10 and 20 mg per day to the subject.

Embodiment 13: The method of embodiment 1, wherein sarilumab and sulfasalazine are administered to the subject.

Embodiment 14: The method of embodiment 13, wherein the sulfasalazine is administered orally. ment 15: The method of embodiment 13, wherein the alazine is administered at between 1000 to 3000 mg per day to the subject.

Embodiment 16: The method of embodiment 1, wherein sarilumab and hydroxychloroquine are administered to the subject.

Embodiment 17: The method of embodiment 16, wherein the hydroxychloroquine is administered orally.

Embodiment 18: The method of ment 16, wherein the hydroxychloroquine is administered at between 200 to 400 mg per day to the subject.

Embodiment 19: The method of any of embodiments 1-18, wherein the subject achieves a 20% improvement in the American College of Rheumatology core set disease index after 12 weeks of treatment.

Embodiment 20: The method of any of ments 1-18, wherein the subject achieves a 50% improvement in the American College of Rheumatology core set disease index after 12 weeks of ent.

Embodiment 21 : The method of any of embodiments 1-18, wherein the subject es a 20% improvement in the American College of Rheumatology core set disease index after 24 weeks of treatment.

Embodiment 22: The method of any of embodiments 1-18, wherein the subject achieves a 50% improvement in the American College of Rheumatology core set disease index after 24 weeks of treatment. ment 23: The method of any of embodiments 1—18, wherein the t achieves a 70% improvement in the American College of Rheumatology core set disease index after 24 weeks of treatment.

Embodiment 24: The method of any of embodiments 1-18, wherein the subject es a lower disease activity score after 12 weeks of treatment than the subject had before treatment.

Embodiment 25: The method of any of ments 1-18, wherein the disease activity score is less than or equal to 2.6 at 12 weeks.

Embodiment 26: The method of any of embodiments 1—18, wherein the disease activity score decreases by greater than 1.2 between start of treatment and 12 weeks.

Embodiment 27: The method of any of embodiments 1—18, wherein the disease ty score is less than or equal to 3.2 at 12 weeks.

Embodiment 28: The method of any of embodiments 1~18, wherein the disease activity score ses by greater than 0.6 between start of treatment and 12 weeks.

Embodiment 29: The method of any of embodiments 1-18, wherein the e activity score is less than or equal to 5.1 at 12 weeks.

Embodiment 30: The method of any of ments 1-18, wherein the subject es a lower disease activity score after 24 weeks of treatment than the subject had before treatment.

Embodiment 31 : The method of any of embodiments 1-18, wherein the disease activity score is less than or equal to 2.6 at 24 weeks.

Embodiment 32: The method of any of embodiments 1—18, wherein the disease activity score decreases by greater than 1.2 between start of treatment and 24 weeks.

Embodiment 33: The method of any of embodiments 1-18, wherein the disease activity score is less than or equal to 8.2 at 24 weeks. 3O Embodiment 34: The method of any of embodiments 1—1 8, wherein the disease activity score decreases by greater than 0.6 between start of ent and 24 weeks.

Embodiment 35: The method of any of embodiments 1-18, wherein the disease activity score is less than or equal to 5.1 at 24 weeks.

Embodiment 36: A method of treating rheumatoid arthritis in a t in need thereof comprising administering to the subject an effective amount of sarilumab and methotrexate, wherein the subject was usly ineffectively d for toid arthritis by administering an anti—TNF-d antagonist.

Embodiment 37: The method of embodiment 36, wherein the subject was previously ineffectively treated for toid arthritis by administering methotrexate. ment 38: The method of embodiment 36, wherein the methotrexate is administered at between 10 to 25 mg per week to the subject.

Embodiment 39: The method of embodiment 36, wherein the subject is a mammal.

Embodiment 40: The method of embodiment 37, wherein the mammal is a human.

Embodiment 41 : The method of embodiment 38, wherein the human is descended from individuals from Asia or the Pacific.

Embodiment 42: The method of embodiment 39, wherein the humans descended from individuals from Asia or the Pacific are administered between 6 and 25 mg per week of methotrexate.

Embodiment 43: The method of embodiment 36, wherein the subject was treated for at least three months with the TNF-d antagonist.

Embodiment 44: The method of ment 36, wherein the subject was intolerant of the TNF-d antagonist.

Embodiment 45: The method of embodiment any one of embodiments 3644, wherein the TNF—d antagonist is a biologic anti-TNF-d antagonist.

Embodiment 46: The method of embodiment 44, wherein the TNF-d antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab and certolizumab.

Embodiment 47: The method of embodiment 36, wherein the sarilumab is administered at between 50 and 150 mg per week.

Embodiment 48: The method of embodiment 36, wherein the sarilumab is administered at between 100 and 200 mg per two weeks.

Embodiment 49: The method of any of embodiments 36—48, wherein the subject achieves a 20% improvement in the American College of Rheumatology core set disease index after 12 weeks of treatment.

Embodiment 50: The method of any of embodiments 36-48, wherein the subject achieves a 50% improvement in the American College of Rheumatology core set disease index after 12 weeks of ent.

Embodiment 51 : The method of any of embodiments 36-48, wherein the subject es a 20% improvement in the American College of Rheumatology core set disease index after 24 weeks of ent.

Embodiment 52: The method of any of embodiments 36-48, n the t achieves a 50% ement in the American College of tology core set e index after 24 weeks of treatment.

Embodiment 53: The method of any of embodiments 36-48, wherein the subject achieves a 70% improvement in the American College of Rheumatology core set disease index after 24 weeks of treatment.

Embodiment 54: The method of any of embodiments 36-48, wherein the subject achieves a lower disease activity score after 12 weeks of treatment than the subject had before treatment.

Embodiment 55: The method of any of embodiments 36-48, wherein the disease activity score is less than or equal to 2.6 at 12 weeks.

Embodiment 56: The method of any of embodiments 36-48, wherein the disease activity score decreases by greater than 1.2 n start of treatment and 12 weeks. ment 57: The method of any of embodiments 36-48, wherein the disease activity score is less than or equal to 3.2 at 12 weeks.

Embodiment 58: The method of any of embodiments 36-48, wherein the disease activity score decreases by greater than 0.6 between start of treatment and 12 weeks.

Embodiment 59: The method of any of embodiments 36-48, wherein the disease activity score is less than or equal to 5.1 at 12 weeks.

Embodiment 60: The method of any of embodiments 36-48, wherein the subject achieves a lower disease activity score after 24 weeks of treatment than the subject had before treatment.

Embodiment 61 : The method of any of embodiments 36-48, wherein the disease ty score is less than or equal to 2.6 at 24 weeks.

Embodiment 62: The method of any of embodiments 36-48, wherein the disease activity score decreases by greater than 1.2 between start of treatment and 24 weeks.

Embodiment 63: The method of any of embodiments 34-45, wherein the disease activity score is less than or equal to 3.2 at 24 weeks.

Embodiment 64: The method of any of embodiments 34—45, wherein the disease activity score decreases by greater than 0.6 n start of treatment and 24 weeks.

Embodiment 65: The method of any of embodiments 34-45, wherein the disease ty score is less than or equal to 5.1 at 24 weeks.

Embodiment 66: A ceutical composition comprising an effective amount of mab and a‘member of the group consisting of omide, sulfasalazine and hydroxychloroquine.

DETAILED DESCRIPTION The disclosure provides pharmaceutical compositions and methods of using these compositions for the treatment of rheumatoid tis (RA) and the improvement of at least one symptom of RA. These compositions include at least one dy that specifically binds human interleukin~6 receptor (hlL-GR) and at least one disease modifying antirheumatic drug (DMARD).

Anti—h/L—6Fi’ Ant/bodies The present disclosure es methods that comprise administering to a patient a human antibody, or an antigen—binding fragment thereof, that binds specifically to hlL-BR. As used herein, the term "hlL~6R" means a human cytokine receptor that specifically binds human eukin-6 (IL—6). in certain embodiments, the antibody that is administered to the patient binds specifically to the extracellular domain of hlL-6R.

The extracellular domain of hlL-6R is shown in the amino acid sequence of SEQ ID NO:1.

Unless specifically indicated ise, the term "antibody," as used herein, shall be understood to ass dy molecules comprising two immunoglobulin heavy chains and two immunoglobulin light chains (i.e., "full antibody molecules") as well as antigen-binding fragments thereof. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered ptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the lation and expression of DNA encoding antibody variable and (optionally) constant domains. Such DNA is known and/or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized. The DNA may be 3O sequenced and manipulated chemically or by using lar biology techniques, for e, to arrange one or more variable and/or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.

Non-limiting examples of n-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single—chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal ition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR)). Other engineered molecules, such as ies, triabodies, tetrabodies and minibodies, are also encompassed within the expression en-binding fragment," as used herein.

An antigen—binding fragment of an dy will typically comprise at least one variable domain. The le domain may be of any size or amino acid composition and will generally comprise at least one CDR which is adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a VH domain associated with a VL domain, the VH and VL domains may be situated ve to one another in any suitable arrangement. For example, the variable region may be dimeric and contain VH-VH, VH-VL or VL—VL . Alternatively, the antigen—binding fragment of an antibody may contain a monomeric VH or VL domain. in certain embodiments, an antigen-binding fragment of an dy may contain at least one variable domain covalently linked to at least one constant domain. Non- limiting, exemplary configurations of variable and constant domains that may be found within an antigen~binding fragment of an antibody of the present invention include: (i) VH'CHi; (ll) VH'CH2§ (iii) VH'CHB; (1V) VH'CHt'CH2§ (V) VH‘CHt-CHz-CHai (Vi) VH'CHZ‘CHS; (Vii) VH-CL; (viii) VL-Cm; (ix) VL-CHZ; (x) VL-CHS; (xi) VL-CH1—CH2; (xii) VL-CH1—CH2—CH3; (xiii) VL— CHZ'CHg; and (xiv) VL-CL. in any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either ly linked to one another or may be linked by a full or partial hinge or linker region. A hinge region may t of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi—flexible linkage between adjacent le and/or constant domains in a single polypeptide molecule. Moreover, an antigen-binding fragment of an antibody of the present invention may comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non—covalent association with one another and/or with one or more monomeric VH or VL domain (e.g., by disulfide bond(s)).

The term "specifically binds," means that an antibody or antigen-binding fragment f forms a x with an antigen that is relatively stable under physiologic conditions. Specific g can be characterized by a dissociation nt of at least about 1x10'E3 M or smaller. in other embodiments, the dissociation constant is at least about 1x10'7 M, 1x10‘8 M , or 1x10‘9 M. Methods for determining whether two molecules specifically bind are well known in the art and include, for example, equilibrium dialysis, surface n resonance, and the like.

As with full dy molecules, antigen-binding fragments may be monospecific or pecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody will lly comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different e on the same antigen. Any multispecific antibody format, ing the exemplary bispecific dy formats disclosed herein, may be adapted for use in the context of an antigen-binding fragment of an antibody of the t invention using routine techniques ble in the art.

In specific embodiments, the antibody or antibody fragment for use in the method of the invention may be a multispecific antibody, which may be specific for different epitopes of one target polypeptide or may contain antigen-binding domains specific for epitopes of more than one target polypeptide. An exemplary bi-specific antibody format that can be used in the context of the present invention involves the use of a first immunoglobulin (lg) CH3 domain and a second lg CH3 domain, wherein the first and second lg CH3 domains differ from one r by at least one amino acid, and wherein at least one amino acid difference reduces binding of the bispecific antibody to Protein Alas compared to a bi-specific dy lacking the amino acid difference. in one embodiment, the first lg CH3 domain binds n A and the second lg CH3 domain ns a mutation that reduces or abolishes Protein A binding such as an H95R modification (by lMGT exon numbering; H435R by EU numbering). The second CH3 may further comprise an Y96F modification (by lMGT; Y436F by EU). Further modifications that may be found within the second CH3 include: D16E, L18M, N448, K52N, V57M, and V82l (by llleT; D356E, L358M, N384S, K392N, V397M, and V422l by EU) in the case of lng antibodies; N448, K52N, and V82l (lMGT; N384S, K392N, and V422| by EU) in the case of lgG2 antibodies; and 015R, N448, K52N, V57M, R69K, E790, and V82l (by lMGT; Q355R, N384S, K392N, V397M, R409K, E4190, and V422l by EU) in the case of lgG4 antibodies. Variations on the bi-specific antibody 3O format described above are contemplated within the scope of the present invention.

In other specific embodiments, the antibody is sarilumab (SAR153191). The heavy chain variable region of sarilumab is shown below as SEQ ID N022.

The light chain variable region of sarilumab is shown below as SEQ ID NO:3.

A "neutralizing” or “blocking” dy, as used herein, is intended to refer to an antibody whose binding to hlL-6R results in inhibition of the biological activity of hlL-6.

This inhibition of the biological activity of hlL-G can be assessed by measuring one or more indicators of hlL-6 biological activity known to the art, such as hlL-6—induced cellular activation and hlL—6 binding to hlL~6R (see examples below).

The fully-human anti—lL-6R dies disclosed herein may comprise one or more amino acid substitutions, insertions and/or deletions in the framework and/or CDR regions of the heavy and light chain variable s as compared to the corresponding germline sequences. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public dy sequence databases. The present invention includes antibodies, and antigen—binding fragments f, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and/or CDR regions are back-mutated to the corresponding ne residue(s) or to a conservative amino acid substitution (natural or non-natural) of the corresponding germline residue(s) (such sequence changes are referred to herein as "germline back-mutations"). A person of ordinary skill in the art, starting with the heavy and light chain variable region sequences disclosed herein, can easily produce numerous antibodies and antigen—binding nts which comprise one or more individual germline back-mutations or combinations f. in certain embodiments, all of the framework and/or CDR residues within the VH and/or VL domains are d back to the ne sequence. in other embodiments, only certain residues are mutated back to the germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FRt or within the last 8 amino acids of FR4, or only the mutated residues found within CDRi, CDR2 or CDR3. Furthermore, the antibodies of the t invention may contain any combination of two or more germline back- mutations within the framework and/or CDR regions, i.e., wherein certain individual residues are mutated back to the germline sequence while certain other residues that differ from the germline sequence are ined. Once obtained, antibodies and antigen-binding nts that contain one or more ne back-mutations can be easily tested for one or more desired property such as, ed binding specificity, increased binding ty, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Antibodies and antigen- binding fragments obtained in this general manner are encompassed within the present invention.

The term ”epitope” refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope. A single antigen may have more than one epitope. Epitopes may be either conformational or linear. A conformational epitope is produced by spatially juxtaposed amino acids from different segments of the linear polypeptide chain. A linear epitope is one produced by adjacent amino acid residues in a polypeptide chain. In certain stance, an epitope may include moieties of saccharides, phosphoryl groups, or sufonyl groups on the n.

The anti—hlL-BR can be sarilumab (SAR153191). in one embodiment, sarilumab is defined as an antibody comprising the heavy chain variable region of SEQ ID NO:2 and the light chain le region of SEQ lD N023.

DMAFz’Ds Disease ing antirheumatic drugs (DMARDs) include rexate, alazine, hydroxychloroquine and leflunomide. According to the compositions and methods of the disclosure, DMARDs can be administered as follows. Methotrexate can be administered from 10 to 25 mg per week orally or intramuscularly. in another embodiment, methotrexate is administered from 6 to 25 mg/week orally or intramuscularly for patients who are from the Asia-Pacific region or who are descended from people who are from the Asia—Pacific region. The Asia-Pacific region includes Taiwan, South Korea, ia, Philippines, Thailand and lndia. in certain embodiments, methotrexate is administered at between 6 and 12, 10 and 15, 15 and 20 and 20 and 25 mg per week. in other embodiments, methotrexate is administered at 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 mg perweek.

Leflunomide can be administered from 10 to 20 mg orally daily. In certain ments, omide can be administered at n 10 and 12, 12 and 15, 15 and 17 and 18 and 20 mg per day. in other embodiments, leflunomide is administered at 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg per day. Sulfasalazine can be administered from 1000 to 3000 mg orally daily. in certain embodiments, alazine can be administered at between 1000 and 1400, 1400 and 1800, 1800 and 2200, 2200 and 2600, and 2600 and 3000 mg per day. in other embodiments, sulfasalazine is administered at 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2800, 2400, 2500, 2600, 2700, 2800, 2900 or 3000 mg per day.

Hydroxychloroquine can be administered from 200 to 400 mg orally daily. In certain embodiments, hydroxychloroquine can be administered at between 200 and 240, 240 and 280, 280 and 320, 320 and 360 and 360 and 400 per day. In other embodiments, hydroxychloroquine can be stered at 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390 or 400 mg per day.

Therapeutic Administration and ations The methods described herein comprise administering a therapeutically effective amount of an anti-hlL—6R antibody and a DMARD to a t. As used herein, the phrase "therapeutically effective amount" means a dose of anti-hlL-GR antibody and a DMARD that results in a detectable ement in one or more symptoms associated with rheumatoid arthritis or which causes a biological effect (e.g., a decrease in the level of a ular biomarker) that is correlated with the underlying pathologic mechanism(s) giving rise to the condition or symptom(s) of rheumatoid arthritis. For example, a dose of lL-6R antibody with one or more DMARDs which causes an improvement in any of the following symptoms or conditions is deemed a "therapeutically effective amount": chronic disease anemia, fever, depression, e, rheumatoid nodules, vasculitis, neuropathy, tis, pericarditis, s syndrome and/orjoint destruction.

A detectable improvement can also be detected using the an College of Rheumatism (ACR) rheumatoid arthritis classification criteria. For example a 20% (ACR20), 50% (ACRSO) or 70% (ACR70) improvement from baseline can be used to show detectable improvement.

The disease activity score (DAS28) can be used to show detectable improvement. DAS28 is a composite score of tender joints count based on 28 joints, a swollen joints count based on 28 joints, a l health assessment and a marker of inflammation which can be assessed by measuring C-reactive protein (CRP) . The disease response can be presented using the European League against Rheumatism (EULAR) response criteria. A good response by this criteria is an improvement of greater than 1.2 in DAS28 score with a present score of greater than or equal to 3.2. A moderate response is an improvement of greater than 0.6 but less than or equal to 1.2 in DAS28 score and a present score of greater than 3.2. Non-response is an improvement of less than 0.6 in DAS28 score and a present score of greater than 5.1.

DAS28 remission is a DAS28 score of less than 2.6. in accordance with the methods of the present invention, a therapeutically effective amount of anti-hlL-BR antibody that is administered to the patient will vary ing upon the age and the size (e.g., body weight or body surface area) of the t as well as the route of administration and other factors well known to those of ordinary skill in the art. In certain embodiments, the dose of anti-hIL-6R antibody administered to the patient is from about 10 mg to about 500 mg. For example, the present invention includes s wherein about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, or more of anti-hlL-SR dy is administered to the patient per week.

In one embodiment, the hlL-GR antibody is administered at 100-150 mg per week. In another embodiment, the hlL-6R antibody is administered at 100-200 mg per ever two weeks. In other ments, the hlL~6R antibody is administered at about 100 or about 150 mg per week. in other embodiments, the hlL—GR antibody is administered at about 100, 150 or 200 mg per every two weeks.

The amount of anti—hIL—BR antibody that is stered to the patient may be expressed in terms of milligrams of antibody per am of patient body weight (I'.e., mg/kg). For example, the methods of the present invention include administering an anti-hIL—SR antibody to a patient at a daily dose of about 0.01 to about 100 mg/kg, about 0.1 to about 50 mg/kg, or about 1 to about 10 mg/kg of patient body weight.

The methods of the present invention include stering multiple doses of an lL-BR antibody to a patient over a ied time course. For example, the anti— hIL-6R antibody can be administered about 1 to 5 times per day, about 1 to 5 times per week, about 1 to 5 times per month or about 1 to 5 times per year. In certain embodiments, the methods of the invention include administering a first dose of anti- hIL—6R antibody to a patient at a first time point, followed by administering at least a second dose of anti-hIL-BR antibody to the patient at a second time point. The first and second doses, in certain embodiments, may contain the same amount of anti-hIL-BR antibody. For instance, the first and second doses may each contain about 10 mg to about 500 mg, about 20 mg to about 300 mg, about 100 mg to about 200 mg, or about 100 mg to about 150 mg of the antibody. The time between the first and second doses may be from about a few hours to several weeks. For e, the second time point (i.e., the time when the second dose is administered) can be from about 1 hour to about 7 weeks after the first time point (i.e., the time when the first dose is administered). ing to n ary embodiments of the present invention, the second time point can be about 1 hour, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks or longer after the first time point. in certain embodiments, the second time point is about 1 week or about 2 weeks.

Third and subsequent doses may be similarly administered throughout the course of treatment of the patient.

The invention provides methods of using therapeutic compositions comprising anti-lL-6R antibodies or antigen-binding fragments thereof and one or more DlVlARDs.

The therapeutic compositions of the invention will be administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, nce, and the like. A multitude of appropriate ations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Pubiishing Company, Easton, PA. These formulations 2O include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LlPOFECTlNTM), DNA conjugates, ous absorption pastes, oil-in-water and water—in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid es containing carbowax. See also Powell et al. "Compendium of excipients for eral formulations" PDA (1998) J Pharm Sci Technol 52:238~311.

The dose may vary depending upon the age and the weight of a t to be administered, target disease, conditions, route of administration, and the like. Various delivery systems are known and can be used to administer the ceutical composition of the invention, e.g., ulation in liposomes, microparticles, microcapsules, receptor mediated endocytosis (see, e.g., Wu etal. (1987) J. Biol.

Chem. 262244294432). Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, al, and oral routes. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be ic or local. The hlL-GR antibody can be administered subcutaneously. The DMARD can be administered orally or intramuscularly.

The pharmaceutical composition can also be delivered in a vesicle, in particular a liposome (see Langer (1990) Science 249215274538). In n situations, the pharmaceutical composition can be delivered in a controlled release system, for example, with the use of a pump or polymeric als. In another embodiment, a controlled release system can be placed in proximity of the composition’s target, thus requiring only a fraction of the systemic dose.

The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, local injection, drip ons, etc. These injectable preparations may be prepared by s publicly known. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt bed above in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc, which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, there are ed, e.g., sesame oil, soybean oil, etc, which may be used in ation with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The ion thus prepared can be filled in an appropriate ampoule.

Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit close include, for example, tablets, pills, es, injections (ampoules), suppositories, etc. The amount of the DMARD contained is generally about 5 to 3000 mg per dosage form in an oral unit dose depending on the specific DMARD used. The amount of the hlL-BR dy contained is generally about 100 to 200 mg per subcutaneous dosage form.

In accordance with the methods disclosed herein, the anti-hlL-6R antibody (or pharmaceutical ation comprising the antibody) can be administered to the patient using any acceptable device or mechanism. For example, the administration can be accomplished using a syringe and needle or with a reusable pen andfor autoinjector delivery . The methods of the present ion include the use of numerous reusable pen and/or autoinjector delivery devices to ster an anti-hlL-BR antibody (or pharmaceutical formulation comprising the antibody). es of such devices include, but are not limited to AUTOPENTM (Owen Mumford, lnc., Woodstock, UK), DISETRONICTM pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25TM pen, HUMALOGTM pen, HUMALlN 70/30TM pen (Eli Lilly and Co., apolis, lN), NOVOPENTM i, ll and ill (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNlORTM (Novo Nordisk, Copenhagen, Denmark), BDTM pen (Becton Dickinson, Franklin Lakes, NJ), NTM, OPTlPEN PROTM, OPTlPEN STARLETTM, and OPTlCLIKTM (sanofi-aventis, Frankfurt, Germany), to name only a few. Examples of disposable pen and/or autoinjector delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the t invention include, but are not limited to the ARTM pen (sancfi—aventis), the FLEXPENTM (Novo Nordisk), and the KWlKPENTM (Eli Lilly), the SURECLICKTM Autoinjector , Thousand Oaks, CA), the F’ENLETTM (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, LP), and the HUMlRATM Pen (Abbott Labs, Abbott Park, IL), to name only a few.

The use of a microinfusor to deliver an anti-hlL-6R antibody (or pharmaceutical ation comprising the antibody) to a t is also contemplated herein. As used herein, the term "microinfusor" means a aneous delivery device designed to 2O slowly administer large s (e.g., up to about 2.5 mL or more) of a therapeutic formulation over a prolonged period of time (e.g., about 10, 15, 20, 25, 30 or more minutes). See, 9.9., US. 6,629,949; US 6,659,982; and Meehan etal., J. Controlled Release 46:107-116 (1996). Microinfusors are ularly useful for the ry of large doses of therapeutic proteins contained within high concentration (e.g., about 100, 125, 150, 175, 200 or more mg/mL) and/or s solutions.

Combination Therapies The present invention es methods of treating rheumatoid arthritis which comprise administering to a t in need of such treatment an anti-hlL-6R antibody in 3O combination with at least one additional therapeutic agent. Examples of additional therapeutic agents which can be administered in combination with an anti—hlL-6R antibody in the practice of the methods of the present invention include, but are not limited to DMARDs, and any other compound known to treat, prevent, or ameliorate rheumatoid arthritis in a human subject. Specific, non-limiting examples of additional therapeutic agents that may be administered in combination with an anti-hlL-SR antibody in the context of a method of the present invention include, but are not limited to methotrexate, sulfasalazine, hydroxychloroquine and leflunomide. In the t methods, the additional therapeutic agent(s) can be administered concurrently or sequentially with the anti-hlL-6R antibody. For example, for concurrent administration, a pharmaceutical formulation can be made which contains both an anti—hlL-BR dy and at least one onal therapeutic agent. The amount of the additional therapeutic agent that is administered in combination with the lL—BR dy in the practice of the methods of the present invention can be easily determined using routine methods known and readily available in the art.

The disclosure of the invention provides for pharmaceutical compositions comprising any of the following: A ition comprising between 100 and 150 mg of sarilumab (SAR153191) and 10-25 mg of methotrexate.

A composition comprising between 100 and 200 mg of sarilumab (SAR153191) and 10-25 mg of methotrexate.

A composition comprising between 100 and 150 mg of sarilumab (SAR153191) and 6-25 mg of methotrexate.

A composition comprising n 100 and 200 mg of sarilumab (SAR153191) and 6-25 mg of methotrexate.

A composition comprising n 100 and 150 mg of sarilumab (SAR153191) and 10—20 mg of leflunomide.

A composition comprising between 100 and 200 mg of sarilumab (SAR153191) and 10—20 mg of leflunomide.

A composition comprising between 100 and 150 mg of sarilumab (SAR153191) and 1000-3000 mg of sultasalazine.

A composition comprising between 100 and 200 mg of sarilumab (SAR153191) and 1000—3000 mg of sulfasalazine.

A ition comprising n 100 and 150 mg of sarilumab (SAR153191) and 200-400 mg of hydroxychloroquine.

A composition sing n 100 and 200 mg of sarilumab (SAR153191) and 200—400 mg of hydroxychloroquine.

The disclosure of the invention provides for methods of improving symptoms associated with rheumatoid arthritis comprising any of the ing: A method comprising administering between 100 and 150 mg of sarilumab (SARi 53191) and 10—25 mg of methotrexate per week to a subject in need thereof.

A method comprising administering between 100 and 200 mg of sarilumab (SAR153191) every two weeks and 10-25 mg of rexate per week to a subject in need thereof.

A method comprising administering between 100 and 150 mg of sarilumab (SAR153191) and 6-25 mg of methotrexate per week to a subject in need thereof.

A method comprising administering between 100 and 200 mg of sarilumab (SAR153191) every two weeks and 6-25 mg of methotrexate per week to a subject in need thereof.

A method comprising administering between 100 and 150 mg of sarilumab (SAR153191) per week and 10-20 mg of leflunomide per day to a subject in need thereof.

A method comprising stering between 100 and 200 mg of mab (SAR153191) every two weeks and 10—20 mg of leflunomide per day to a t in need thereof.

A method comprising administering between 100 and 150 mg of sarilumab (SAR153191) per week and 1000-3000 mg of sulfasalazine per day to a subject in need thereof.

A method comprising administering between 100 and 200 mg of sarilumab (SAR153191) every two weeks and 1000—3000 mg of sulfasalazine per day to a subject 2O in need thereof.

A method comprising administering between 100 and 150 mg of mab (SAR153191) per week and 200-400 mg of hydroxychloroquine per day to a subject in need thereof.

A method comprising administering between 100 and 200 mg of sarilumab (SAR153191) every two weeks and 200-400 mg of hydroxychloroquine per day to a subject in need thereof.

Biomarkers The t disclosure es methods of treating rheumatoid arthritis by administering to a patient in need of such treatment a eutically effective amount of a human antibody or antibody binding nt thereof which specifically binds to hlL-6R and a eutically effective amount of one or more DMARDs, wherein the level of one or more RA-associated biomarkers in the patient is ed (e.g., increased, decreased, etc, as the case may be) following administration. in a related aspect, the present invention includes methods for decreasing an RA-associated biomarker in a patient by administering to the patient a therapeutically-effective amount of a human dy or antigen-binding fragment thereof which specifically binds to hlL- BR and a eutically effective amount of one or more .

Examples of RA—associated kers e, but are not limited to, e.g., high— sensitivity C-reaotive protein ), serum amyloid A (SAA), erythrocyte sedimentation rate (ESR), serum hepcidin, interleukin-6 (lL—6), and hemoglobin (Hb).

As will be appreciated by a person of ordinary skill in the art, an increase or decrease in an RA-associated biomarker can be determined by comparing the level of the biomarker measured in the patient at a defined time point after administration of the anti-IL-SR dy to the level of the biomarker measured in the patient prior to the administration (i.e., the "baseline measurement"). The defined time point at which the biomarker can be measured can be, e.g., at about 4 hours, 8 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 15 days, 20 days, 35 days, 40 days or more after administration of the anti-hlL-6R antibody.

According to certain embodiments of the present invention, a patient may exhibit a decrease in the level of one or more of hsCRP, SAA, ESR and/or in following administration of an anti—hlL-6R antibody to the patient. For example, at about week 12 following weekly administration of lL-6R antibody and one or more DMARDs the t may t one or more of the following: (i) a decrease in hsCRP by about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more; (ii) a decrease in SAA by about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more; (iii) a decrease in ESR by about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or more; and/or (iv) a decrease in in by about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more.

According to certain other embodiments of the present invention, a patient may exhibit an increase in the level of one or more of Hb or lL—6 following administration of an anti-hlL-6R antibody and one or more DMARDs to the patient. For example, at about week 12 following weekly administration of anti-hlL-6R antibody and one or more DMARDs the patient may exhibit one or more of the following: (v) an increase in Hb by about 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0% or more; and/or (vi) an increase in lL-6 by about 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 650%, 700%, 750%, 800% or more.

The present invention includes methods for determining whether a subject is a suitable patient for whom administration of an anti—hlL-6R antibody would be beneficial.

For example, if an individual, prior to receiving an anti-hlL—6R antibody and/or one or more DMARDs, exhibits a level of an RA-associated biomarker which signifies the disease state, the dual is therefore identified as a suitable patient for whom administration of an anti-hlL-6R antibody would be beneficial. ing to certain exemplary embodiments, an individual may be identified as a good candidate for anti- hlL-BR/DMARD therapy it the individual exhibits one or more of the following: (i) a level of hsCRP greater than about 4 mg/L (e.g., about 4.5 mg/L, about 5.0 mg/L, about 5.5 mg/L, about 6.0 mg/L, about 7.0 mg/L, about 10.0 mg/L, about 15.0 mg/L, about 20.0 mg/L, or more); (ii) a level of SAA greater than about 3800 ng/mL (e.g., about 4000 ng/mL, 4500 ng/mL, about 5000 ng/mL, about 5500 ng/mL, about 6000 ng/mL, about 10,000 ng/mL, about 20,000 ng/mL, about 25,000 ng/mL, about 30,000 ng/mL, about ,000 ng/mL, about 40,000 ng/mL, about 45,000 ng/mL, or more); (iii) an ESR greater than about 15 mm/hr (e.g., about 16 mm/hr, about 17 mm/hr, about 18 mm/hr, about 19 mm/hr, about 20 mm/hr, about 21 mm/hr, about 22 mm/hr, about 25 mm/hr, about 30 mm/hr, about 35 mm/hr, about 40 mm/hr, about 45 mm/hr, about 50 mm/hr, or more); and/or (iv) a level of hepcidin greater than about 60 ng/mL (e.g., about 62 ng/mL, about 64 ng/mL, about 68 ng/mL, about 70 ng/mL, about 72 ng/mL, about 74 ng/mL, about 76 ng/mL, about 78 ng/mL, about 80 ng/mL, about 82 ng/mL, about 84 ng/mL, about 85 ng/mL, about 90 ng/mL, about 95 ng/mL, about 100 ng/mL, about 105 ng/mL, or more).

Additional ia, such as other clinical indicators of RA, may be used in combination with any of the foregoing RA-associated biomarkers to identify an individual as a suitable candidate for lL-BR therapy.

Patient Population In certain embodiments, the methods and compositions described herein are stered to specific patient populations. These populations include patients that have previously been treated for rheumatoid arthritis with treatment regimens other than the combination of an anti—hlL-GR antibody and one or more DMARDs. These treatment regimens include anti-TNF-d therapy, e.g., biologic anti-TNF-o treatment regimens. Biologic anti-TNF-d antagonists include etanercept, intliximab, adalimumab, golimumab and izumab pegol. These treatment regimens also include DMARD therapy in the absence of anti-hIL-6R antibody.

DMARDs used in this therapy e methotrexate, sulfasalazine, hydroxychloroquine and omide. The DMARDs may be stered alone or in combination with r therapy that is not an anti—hlL-BR antibody. In a specific embodiment, the previous treatment n was methotrexate. In another embodiment, treatment with methotrexate is maintained in patient treated with an anti- hlL-6R antibody. In certain embodiments, the patient has usly been administered both anti-TNF-d and DMARD ies. The therapies may be med sequentially in any order or simultaneously. in certain embodiments, these therapies have been received by the patient within 2 years prior to receiving the combination of an anti—hlL— 6R antibody and one or more DMARDs. in other embodiments, these therapies have been received within 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 years prior to receiving the combination of an anti—hlL~6R antibody and one or more DMARDs.

In certain embodiments, the methods and compositions described herein are administered to specific patient populations that have received one or more of the ent regimens described above wherein these treatments have not been effective.

As used herein, a treatment has not been effective when a dose of anti-TNF—d and a DMARD do not result in a detectable improvement in one or more symptoms associated with rheumatoid arthritis or do not cause a biological effect (e.g., a decrease in the level of a particular biomarker) that is correlated with the underlying pathologic mechanism(s) giving rise to the condition or symptom(s) of rheumatoid tis.

In another e, a treatment has not been effective when a dose of anti- TNF-d does not result in a detectable ement in one or more symptoms associated with rheumatoid arthritis or does not cause a biological effect (e.g., a decrease in the level of a particular biomarker) that is correlated with the underlying pathologic mechanism(s) giving rise to the condition or symptom(s) In another example, a treatment has not been effective when a dose of anti-hlL- 6R antibody and a DMARD that does not result in a detectable ement in one or more symptoms associated with rheumatoid arthritis or which does not cause a biological effect that is correlated with the underlying pathologic mechanism(s) giving rise to the condition or m(s) of rheumatoid arthritis. in certain embodiement, sarilumab is administered to a t who has previously been inefficiently treated with a DMARD. As used herein, a treatment with a DMARD has not been effective when a patient still presents an “active disease” after treatment. Patients t an active disease when they exhibit at least 8 of 68 tender joints and 6 of 66 n joints, and high sensitivity C-reactive n (hs-CRP) >10 mg/L (>1.0 mgidL). in a ic embodiment, patients have previously been inefficiently d with MTX. in such example, patients may have received continuous treatment with MTX 10 to 25 mg/week (or per local labeling requirements if the dose range differs) for at least 12 weeks and on a stable dose of MTX for a minimum of 8 weeks and still present a moderate-to-severely active RA, defined as: (i) at least 8 of 68 tender joints and 6 of 66 swollen joints, and (if) high sensitivity C-reactive protein (hs-CRP) >10 mg/L (>1.0 mg/dL).

For example, a treatment which does not cause an improvement in any of the following symptoms or conditions is deemed ineffective: chronic disease anemia, fever, depression, fatigue, rheumatoid nodules, vasculitis, neuropathy, scleritis, pericarditis, Felty’s me and/or joint destruction.

A detectable improvement can also be detected using the American e of Rheumatism (ACR) rheumatoid arthritis classification ia. For example a 20% (ACRZO), 50% (ACRSO) or 70% (ACR70) improvement from ne can be used to show detectable improvement.

The e activity score (DASZS) can be used to show detectable improvement. DAS28 is a composite score of tender joints count based on 28 , a swollen joints count based on 28 joints, a general health assessment and a marker of inflammation which can be assessed by measuring C-reactive protein (CRP) levels.

The disease response can be presented using the European League t Rheumatism (EULAR) response criteria. A good response by this criteria is an improvement of greater than 1.2 in DA828 score with a present score of greater than or equal to 3.2. A moderate response is an improvement of r than 0.6 but less than or equal to 1.2 in DAS28 score and a present score of greater than 3.2. Non—response is an improvement of less than 0.6 in DA828 score and a present score of greater than .1. DA828 remission is a DAS28 score of less than 2.6. A detectable improvement can also be shown by measuring an improvement in any of the components of the DAS28 score.

EXAMPLES Example 1. Combination of Sarilumab and Methotrexate is Effective in Treatment of Rheumatoid Arthritis in Patients where Methotrexate Treatment is Ineffective.

A worldwide, double-blind, placebo-controlled, randomized study was performed in patients with rheumatoid tis with an inadequate response to methotrexate (MTX). Patients who were included in the study had the following ia. Patients needed to have active disease defined as: at least 6 of 66 swollen joints and 8 of 68 tender joints and; hs-CRP > 6 mg/L. Patients also needed to have had continuous ent with methotrexate (MTX) — 10 to 25 mg/wk (or 6 to 25 mg/wk for patients within Asia-Pacific region for 12 weeks.

The study includes two parts. The first part (Part A) of the study was a 12-week, 6-arm dose-ranging part intended to select the two best dose regimens based on efficacy (reduction in signs and ms) and safety. The second part (Part B) of the study is a 52—week part to confirm the efficacy and safety of these two selected dose regimens on reduction in signs and symptoms, inhibition of progression of structurai damage, improvement in physical function, and induction of major clinical response.

The operationally seamless design nature of this study resides in the fact that Part B is starting to test patients just after the last patient was randomized in Part A without waiting for the dose selection based on its resuits. Thus part B patients belong to 2 distinct cohorts according to the time of their enroilment: Cohort 1 of patients randomized before the dose selection: these patients are randomized into six arms (as the ones of Part A). After dose selection, the patients randomized in the two selected doses and the placebo regimens continue the k trial but those randomized in the three other arms are discontinued from the present study but proposed to join an open iabel extension (see LTSt 1210).

Cohort 2 of patients randomized after the dose selection: these patients are randomized into three arms, the two selected ones and o.

PartA ts were assessed at a screening visit for confirmation of the diagnosis, disease activity, eligibility to the study and verification of concomitant therapy.

Complete examination and tory tests including hematology, chemistry profile, lipid profile, liver enzymes and acute phase reactants, HbAic, hepatitis B and C and serum pregnancy test for women of childbearing potential were performed. An ECG evaluation was also performed. A PPD test and QuantiFEFtON were med to exclude any tuberculosis as weli as a chest X-ray (if a documented negative X~ray performed in the last 3 months is not available).

After mation of iiity, patients were randomized in a balanced manner, in this international multi—center, doubie-biind, parallel group placebo—controlled, 12- week study treatment of six arms of SAR153191 or placebo given subcutaneously weekly with MTX apy. The doses are shown in Figure 1.

Methothrexate was administered for each patient as it had been before the study. This was at 10 to 25 mg/wk, or 6 to 25 mg/wk for ts within Asia-Pacific ; Taiwan, South Korea, Maiaysia, pines, Thailand, and india.

During the first visit, patients were reminded of the list of prohibited medications, and that they should continue taking MTX at their current stable dose untii the end of the study with folic acid as per local recommendation to t MTX toxicity. The patients were trained to prepare and self administer the IMP and were reminded to have injection strictly 7 days apart. At g time points occurring outside site visits, SAR153191 was injected by the patient himself, by a trained professional caregiver or by a trained qualified person.

Patients had six additional visits at weeks 2, 4, 6, 8, 10, and 12. Efficacy assessment and laboratory test including hematology, try profile, lipid profile, liver enzymes and acute phase reactants were ed throughout the study to allow calculation of the main efficacy , and follow up of safety aspects. At randomization visit and at Week 2, 4, 8, and 12, a complete joint examination for tender joint count and swollen joint count was performed by an assessor independent from the Investigator and the t’s data, in order to calculate the ACR score (primary end- point). In order to maintain the blind, the Investigator, the r and the patient will be blind to CRP and serum lL6 levels during the study.

A close monitoring of adverse events including potential infections assessed in part by monitoring of body temperature was performed at every visit. Presence of tuberculosis was checked through specific patient assessment (check for any signs or symptoms, or contact with active TB). Neurological abnormalities (history and physical examination) or autoimmune diatheses (ANA, ds—DNA antibodies) were tested at 2O baseline and end of ent visit.

Specific blood and urine samples were taken during the study to test ial biomarkers that may be predictive of disease response or adverse events. These included a single sample for DNA (after the patient has signed a specific informed consent form) and several samples obtained sequentially throughout the study for RNA expression-profiling and protein biomarker analyses. Samples were also ted at appropriate time points for pharmacokinetic parameters and dy to SAR153191.

Patients prematurely discontinued were evaluated at an end of treatment visit with complete clinical and laboratory evaluation. They were considered as non- responders with regard to the ACR score.

At the end of treatment visit, all patients were scheduled to complete a Post Treatment Follow—up Visit. Patients who had ted the treatment period were proposed to enter an open-label long-term safety extension study with SARf 53191.

Human ts treated with sarilumab (REGN88/SAR153191) in combination with the standard RA treatment, methotrexate (MTX), achieved a significant and clinically meaningful improvement in signs and symptoms of moderate-to-severe rheumatoid arthritis (RA) compared to patients treated with MTX alone. The 306- t, dose-ranging, multinational, randomized, multi-arm, double-blind, placebo- controlled study was performed that compared five ent dose regimens of sarilumab in combination with MTX to placebo plus MTX. The primary endpoint of the study was the proportion of patients achieving at least a 20% ement in RA symptoms (ACRZO) after 12 weeks.

A dose response was observed in patients receiving sarilumab in combination with MTX. An ACR2O response after 12 weeks was seen in 49.0% of ts receiving the lowest sarilumab dose regimen and 72.0% of patients receiving the highest dose regimen compared to 46.2% of patients ing placebo and MTX (p:0.02, corrected for multiplicity, for the t sarilumab dose regimen) (Figure 2). The most common e events (>5%) ed more frequently in active—treatment arms included infections (non-serious), neutropenia, and liver—function test abnormalities. The types and frequencies of adverse events were consistent with those previously reported with lL—6 inhibition. The incidence of serious e events among the five sarilumab treatment groups and the placebo group were comparable.

Sarilumab also demonstrated significant benefit compared to placebo in secondary endpoints, including ACR 50, ACR 70, and DAS 28 scores, additional measures of clinical activity used in RA trials. More specifically: - An ACRSO response after 12 weeks was seen in 22% of patients receiving the lowest sarilumab dose regimen and 30% of patients receiving the highest dose regimen compared to 15% of patients receiving placebo and MTX (Figure 3) - The ACR7O was also significantly higher in the 200 mg q2w group versus placebo. An ACR7O response after 12 weeks was seen in 16% of patients receiving the highest dose regimen compared to 2% of ts receiving o and MTX (Figure 3).

These results provide evidence that lL-GR blockade with sarilumab represents a promising new anti-inflammatory investigational y for reducing RA disease symptoms.

Part B Patients will be assessed at a screening visit for confirmation of the diagnosis disease activity, eligibility to the study and verification of concomitant y. The investigator will check that the patient is either positive anticyclic linated peptide dy (CCP) or positive rheumatoid factor (RF) or that he/she has a med bone erosion on an X-ray. If necessary, for patients who are both GOP and RF negative and have no X-ray, a centrally-reviewed screening X-ray will be med and considered also as the baseline X—ray assessment for the study.

Cohort 1: Patients randomized before the dose selection.

Recruitment in for the long term safety ion study will start just after the last patient has been randomized in Part A. After confirmation of eligibility, patients will be randomized, in a balanced manner stratified by prior biologic use and by regions, in an international, multi—center, double-blind, parallel group placebo-controlled, study treatment of 6 arms of 191 (5 active dose regimens) or placebo given subcutaneously weekly with MTX cotherapy.

At the beginning of every patient visit for Cohort 1 patients, the investigator will check through lVRS list that the patient is still “eligible” for the study, i.e., that the patient is not to be discontinued because of randomization in a nonselected arm. indeed, when the pivotal dose regimens are selected from Part A, only patients ized in the corresponding arms or placebo will still be considered eligible for the study and will continue in the study for a total of 52 weeks. The other patients mized in the nonselected dose regimens) will be ered no longer eligible by lVRS. The investigator will propose these patients to participate in an open extension study with 191 at the highest dose regimen available at the time the patient is enrolled.

The initial randomization will remain blinded for all patients.

Cohort 2: Patients randomized after the dose selection — Pivotal Part.

At day 1, after confirmation of eligibility, patients will be randomized, in a balanced manner stratified by prior biologic use and by regions, in an international, multi—center, double-blind, parallel group, placebo-controlled, study of 3 arms of SAR153191 (2 pivotal dose regimens) or placebo given aneously with MTX cotherapy.

Both Cohorts: in either cohort, patients will be evaluated at Week 2, at Week 4, and every 4 3O weeks until Week 28 and then every 8 weeks until Week 52 for cy and safety ments and laboratory tests.

The same procedures as described in Part A will be applied in Part B. in addition, an X-ray evaluation of the hands and feet joints will be performed at baseline, Week 24 and Week 52. Radiographs de-identified of any patient information will be sent to central readers for calculation of the Sharp score (a specific scoring system of joints ction). Health ic assessments will be also added such as SF-36.

From Week 16, ts with lack of efficacy defined as less than 20% improvement from baseline in either swollen joints count (SJC) or tender joints count (TJC) for 2 consecutive visits, or any other clear lack of cy based on Investigator judgment will be proposed to be rescued with open—label SAR153191 highest available dose at the time of transfer into the rescue treatment arm, and will continue in the study ing to their planned visit schedule. Blood samples for laboratory analysis will be taken two weeks after the switch for safety purpose. They will be considered nonresponders for the primary endpoint (ACRZO). These patients will stay in the study and continue all visits.

In ed countries, patients who meet lack of efficacy criteria at Part B treatment Visit 7/Week 16, or thereafter, will be permanently discontinued from treatment, and will not be eligible to participate in the open treatment rescue arm.

Instead, the patients will have a follow-up visit to evaluate safety 6 weeks after the End of Treatment visit.

For any patient who discontinues prematurely or who is prematurely rescued with open 191, an additional X-ray evaluation will be performed at the time of withdrawal or rescue, unless a study X—ray assessment has been performed within the preceding 3 months (a window of 3 months between 2 X-ray evaluations should be considered to avoid over X-ray exposure).

Patients completing Part B (including those in the open-label rescue arm) will be proposed to be rolled into an open label extension study at the maximum dose n at the time of enrollment. All patients will be scheduled to te the Post Treatment Follow-up Visit. If the patient agrees to enter the SAR153191 open-label long—term ion study, and is confirmed to be eligible, the Post Treatment Follow-up Visit will not be completed. e 2. Combination of Sarilumab and DMARDs are Effective in Treatment of 3O Rheumatoid Arthritis in Patients where TNF-or nist and Methotrexate Treatment are Ineffective.

A worldwide, double-blind, placebo-controlled, randomized study was performed in patients with rheumatoid arthritis with an inadequate response to methotrexate (MTX) and at least one TNF-a antagonist. Patients who were included in the study had the following criteria. Patients had, in the opinion of the investigator, an inadequate response to at least one TNF-o antagonist, after being treated for at least 3 months in the last 2 years, or patients being intolerant to at least 1 TNF-d antagonist, resulting in discontinuation. TNF-o antagonists included etanercept, infliximab, adalimumab, golimumab and/or certolizumab pegol. Patients needed to have active disease d as: at least 6 of 66 swollen joints and 8 of 68 tender joints and; hs-CRP 28 mgiL.

Patients also needed to have had uous treatment with one or a ation of DMARDs for at least 12 weeks prior to baseline and on a stable dose(s) for at least 6 weeks priorto screening. These DMARDs ed methotrexate (MTX) - 10 to 25 mg/wk (or 6 to 25 mg/wk for patients within Asia—Pacific region; leflunomide (LEF) — 10 to 20 mg daily; sulfasalazine (SSZ) - 1000 to 3000 mg daily; or hydroxychloroquine (HCQ) — 200 to 400 mg daily.

Table 1 - Groups and forms for both investigational medicinal product and noninvestigational medicinal product Group Treatment Sarilumab Sarilumab Placebo Background 150 mg 200 mg medication as erapy or in combination I BT + 1 SC Including: sarilumab ion — Methotrexate — 10 to 25 every 2 mg/wk (or 6 to 25 mg/wk weeks (q2w) for patients within Asia- Pacitic region) with tolic/folinic acid supplement - Leflunomide — 10 to 20 mg daily - Sulfasalazin — 1000 to 3000 mg daily — Hydroxychloroquin — 200 to 400 mg daily I] BT + -— 1 SC -— Same as above sarilumab ion lll BT + -- -- 1 SC Same as above placebo q2w injection From Week 12 patients with lack of efficacy defined as less than 20% improvement from baseline in both swollen joint count and tender joint count for 2 consecutive visits will be proposed to be rescued with open label mab at the highest dose in the trial. These patients will continue the trial according to the schedule of visits.

BT = background therapy; q2w = every other week; SC = subcutaneous Subcutaneous administration will occur in the abdomen or thigh. Each dose will be self-administered (whenever possible), in a single injection. The SC ion sites can be alternated between the 4 quadrants of the abdomen t the navel or waist area) or the thigh (front and side).

Patients and/or their nonprofessional caregivers will be trained to prepare and administer IMP at the start of the double-blind ent period. This training must be nted in the patients’ study tile. The study nator or designee may administer the first injection sing the initial dose as part of the training procedure on Day 1 (Visit 2). On days when the patient has a study visit, the IMP will be administered following clinic procedures and blood collection. For doses not given at the study site, diaries will be provided to record information pertaining to these injections; these diaries will be kept as source data in the patients’ study file. if the patient is unable or unwilling to administer lMP, ements must be made for qualified site personnel and/or caregiver to administer IMP for the doses that are not scheduled to be given at the study site. it the study visit is not performed at the site as scheduled, the dose will be administered by the patient and/or their caregiver(s) as scheduled.

Treatment will last for 24 weeks. From Week 12, patients with lack of efficacy defined as less than 20% ement from baseline in both SJC and TJC for 2 consecutive visits will be proposed to be rescued with open label sarilumab at the highest dose in the trial. These patients will continue the trial according to the schedule of visits. in this study, sarilumab is administered on top of DMARD therapy, considered as a background therapy. All patients should continue to receive continuous treatment with one or a combination of logic DMARD(s) as background therapy for at least 12 weeks prior to baseline and on a stable ) for at least 6 weeks prior to screening: . methotrexate (MTX) - 10 to 25 mg/wk (or 6 to 25 mg/wk for patients within Asia-Pacific region) with folic/folinic acid supplement - leflunomide (LEF) — 10 to 20 mg daily - sulfasalazin (SSZ) — 1000 to 3000 mg daily - hydroxychloroquin (HCQ) — 200 to 400 mg daily Each DMARD dose will be recorded throughout the study on the case report form. At any time, the DMARD dose can be reduced for safety or tolerability reason.

Any change in dose and the start date of the new dose should be recorded on the e- CRF at every visit. DMARD(s) will not be dispensed or supplied by the Sponsor as an IMP.

All patients taking MTX will receive folic/tolinic acid according to local recommendation in the country where the study is conducted. The dose, route and administration schedule of tolic/folinic acid will be recorded with concomitant tions.

Sarilumab and matching placebo will be provided in identically matched glass prefilled syringes. Each prefilled syringe ns 1.14 mL of sarilumab (SAR153191) or matching placebo solution.

A list of treatment kit numbers will be generated. A randomization list will be generated by the interactive voice response system (lVRS). Both the randomization and ent kit lists will be loaded into the lVRS.

The treatment kit numbers will be obtained by the Investigator at the time of t ization and subsequent patient scheduled visits via lVRS that will be ble 24 hours a day.

In accordance with the double-blind design, investigators will remain blinded to study treatment and will not have access to the randomization (treatment codes) except under circumstances described in n 8.7.

Patients will be randomized to one of the treatment arms via a centralized randomization system using an IVRS. A patient will be considered randomized when the ent number has been provided by the lVRS.

At the ing visit, Visit 1, the site coordinator will contact the IVRS to obtain a patient number for each patient who gives ed consent. Each patient will be allocated a patient number associated with the center and allocated in chronological order in each center.

The treatment assignment will be allocated to the patient according to the central randomization list via the lVRS stratified by region and number of previous anti- TNFs (1 versus > 1) . At Visit 2 (Day 1), after confirming the t is eligible for entry into the treatment period, the site coordinator will contact the lVRS in order to receive 3O the first treatment assignments (kit numbers). Patients will be randomized to receive either one of the 2 treatment arms of sarilumab or its ng placebo. The randomization ratio is 1:1 :1 (sarilumab 150 mg 2 mab 200 mg : matching placebo).

At subsequent dispensation visits during the treatment period, the site coordinator will call lVRS to obtain the subsequent treatment kits assignment. A confirmation fax/e-mail will be sent to the site after each assignment.

A randomized patient is defined as a patient who is registered and assigned a randomization number from the lVRS, as documented from the lVRS log file. IMP will also be recorded and tracked on the center IMP inventory forms.

The compositions and methods of the present sure are not to be d in scope by the specific embodiments describe herein. indeed, various modifications of the invention in addition to those described herein will become apparent to those d in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

THE

Claims (11)

CLAIMS :

1. Use of an antibody or binding fragment thereof in the manufacture of at least one medicament for the treatment of rheumatoid arthritis in a t previously ineffectively trea ted for rheumatoid arthritis by the administration of methotrexate and previously ineffectively d for rheumatoid arthritis by the administration of a TNF -α antagonist , wherein the antibody or g fragment thereof comprises the heavy chain variable region of SEQ ID No. 2 and the light chain variable region of SEQ ID No. 3, and wherein the at least one medicament is formulated for stration to the pa tient in a dosing regime that provides between 100 mg and 200 mg of said antibody or binding fragment thereof, to the t; the dosing regime comprises at least one dosing cycle that is designed to provide the effective delivery of the at least one medi cament in an effective amount per two weeks, and the dosing cycle is repeated for as long as necessary to achieve a desired ical response in a subject , and wherein the antibody of binding fragment thereof is formulated for subcutaneous stration .

2. The use according to claim 1, wherein the at least one medicament includes methotrexate .

3. The use according to claim 2, wherein the dosing regime provides a dosage of methotrexate of between 6 -25 mg per week.

4. The use acc ording to any one of the p receding claims wherein the dosing regime provides a dosage of said antibody or fragment f o f 150 mg per two weeks or 200 mg per two weeks.

5. The use according to any one of the previous claims, wherein the subject is capable of achieving at least a 20 % improvement in the American College of Rheumatology core set disease index after treatment.

6. The use according to any one of claims 1 to 4, wherein the subject is capable of ing at least a 50% improvement in the an College of Rheumatology core set disease index after treatment.

7. The use according to any one of claims 1 to 4, wherein the subject is capable of ing at least a 70% improvement in the American College of Rheumatology core set disease index after treatment.

8. The use according to any one of claims 5 to 7, wherein the treatment lasts for at least 12 weeks.

9. The use according to any one of the previous claims, wherein the subject was usly ineffectively treated for rheumatoid arthritis by the administration of a TNF -α antagonist selected from the group consisting of etanercept, infliximab, adalimumab, golimumab and/or cert olizumab pegol.

10. The use according to claim 9, wherein the subject was d with an anti - TNF -α antagonist for at least 3 months, or the subject was intolerant to at least one TNF -α antagonist.

11. The use ing to any one of the previous claims, wherein the antibody is sarilumab. RON PHARMACEUT ICALS, INC SANOFI WATERMARK PATENT AND TRADE MARKS ATTORNEY S P38820NZ00